10.2478/v10063-008-0027-2
ANNALES
UNIVERSITATIS MARIAE CURIE-SKŁODOWSKA
LUBLIN – POLONIA
VOL. LXIII, 4
SECTIO AA
2008
Biomedical applications of the Langmuir monolayer technique♣
K. Hąc-Wydro and P. Dynarowicz-Łątka
Jagiellonian University, Faculty of Chemistry, Ingardena 3,
30-060 Kraków, Poland
The modeling of natural membranes is a consequence of their complex
structure. The paper describes different approaches used to model
biomembranes, and emphasizes the advantages of applying the Langmuir
monolayer technique in this aspect.
1. INTRODUCTION
The technique of monomolecular layers formed at the aqueous solution-air
interface, termed Langmuir (or insoluble, spread, floating) monolayers (films) is
based on spreading an aliquot of an amphiphile of interest in organic, volatile
and water-immiscible solvent (such as chloroform) on water surface. After
solvent evaporation, the free surface is entirely covered by a monomolecular
layer of an amphiphile, which can be compressed to the desired surface
pressure/mean molecular area by sliding barriers, using the Langmuir trough [1].
The use of the Langmuir method allows for a continuous control of both quality
of the surface and such parameters as molecular packing, physical state, lateral
pressure and composition. A thorough understanding of monolayer behavior at
the free water surface is essential for exploiting so-called Langmuir-Blodgett
(LB) technique [2], which basically involves the formation of a monolayer film
on water with its subsequent transfer (either by vertical or horizontal dipping)
onto a solid substrate, as a viable route for making highly ordered, defectless
ultrathin films with controllable molecular orientation, thickness and
architecture. These outstanding opportunities of the LB method have led to an
♣
Paper dedicated to Professor Emil Chibowski on the occasion of his 65th birthday
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K. Hąc-Wydro and P. Dynarowicz-Łątka
international effort to exploit such films in optical devices, highly specific
chemical sensors or molecular electronics.
It is quite understandable that the application of Langmuir films, because of
the fact that they are formed on water, is much more limited as compared to LB
films. However, there is a field, in which they are very important, i.e. biomedical
sciences, like biology, pharmacy and medicine. Lipids monolayers form an
excellent model of one leaflet of a cellular membrane and therefore the
Langmuir technique is successfully applied to studying the properties of
biomembranes, various processes occurring on membrane level or the
interactions between membrane components. Such a technique is also useful tool
for investigating of the mechanism of action of amphiphilic drugs active on
membrane level or the effect of other biomolecules on biomembrane. This paper
is aimed at providing examples for successful applications of the Langmuir
technique in this area.
2. MODELING OF A CELLULAR MEMBRANE
The natural membrane is composed of different class of lipids (mainly
phospholipids, sphingolipids and sterols) and proteins organized into the
structure described generally by so-called fluid-mosaic model proposed by
Singer and Nicolson in 1972 [3,4]. The framework of membrane builds a lipid
bilayer, which is a “fluid” part of this structure. The “mosaic”, on the other hand,
is made by proteins embedded into the lipids’ framework. Proteins either
penetrate the bilayer (integral proteins) or are localized on the surface of leaflets.
The latter may be located loosely on the surface layer (peripheral proteins) or
bound covalently to membrane lipids (lipid-anchored proteins). The fluid-mosaic
model represents general structure of a biomembrane; however, its organization
is still being investigated. For example, the research performed in last decades
proved the existence of microdomains enriched in cholesterol, called “lipid
rafts” [5]. This finding significantly changed previously accepted view on
homogeneous distribution of lipids in natural membranes. The cellular
membrane is characterized by a highly dynamic structure, in which both
phospholipids and proteins are mobile and able to interact. Membrane is also
asymmetric in structure – this means that the composition of the two membrane
layers is different. Generally, in the outer layer phosphatidylcholines and
sphingomyelins are mainly present, while the inner layer contains
phosphatidylethanolamines and phosphatidylserines [4]. Obviously, the
composition of a membrane (lipids type and the lipid-to-protein proportion)
depends on the species of organism, kind of an organ and tissue, type of a cell or,
within the cell, on the type of organelle.
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The cellular membrane is not only a physical barrier separating the inside of
the cell from the outside, but allows cells to selectively interact with their
environment [4,6]. Apart from its importance in vast array of cellular processes
(such as ions and metabolites transport, communication and regulation
processes), it makes a site of a number of drugs acting at the membrane level of a
living cell. Antimicrobial peptides, such as alamethicin [7] or gramicidin [8],
polyene macrolide antibiotics (for example amphotericin B or nystatin [9]) or
alkyl-lysophospholipids (a new generation anticancer drugs, like miltefosine [10]
or edelfosine [11]) are good examples of molecules, the physiological activity of
which occurs at a lipid membrane interface. For these particular kinds of drugs,
studies of their influence on the cell membranes are of utmost importance. For
this purpose, several approaches are possible. The drug-membrane interactions
can be investigated with living cells or natural membranes isolated from cells.
However, the foregoing methods are characterized by complexity of both the
experimental procedures and the results obtained, and moreover, provide only
global information on the membrane. Therefore they are unsuitable for studying
specific aspects of a given phenomena occurring at membrane level (e.g. lipid –
protein or drug – lipid interactions). For these kinds of investigation the best
choice is to use one of membrane models. They are briefly discussed below.
glycolipid
proteins
phospholipid
bilayer
sterol
Fig. 1. Schematic representation of a biomembrane structure, according to the fluidmosaic model.
The most widely used membrane models are lipid vesicles (liposomes), which
consist of an aqueous space closed in a lipid bilayer(s) (Figure 2). Depending on
the number of layers surrounding the aqueous core the liposomes are classified
as multillamelar vesicles and unilamellar vesicles [12,13].
These structures were discovered in the sixties of the preceding century upon
microscopic observation of phospholipids dispersion in water [12,13]. Originally
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K. Hąc-Wydro and P. Dynarowicz-Łątka
prepared liposomes were formed from natural phospholipids. Later, other
amphiphatic compounds were found to be useful for making liposomes and
artificial vesicles were prepared from synthetic amphiphiles. Currently,
depending either on the type of an amphiphile used or on the application of
vesicles, the liposomes are specifically named (niosomes, nanoparticles,
nanospheres) [12,13]. To distinguish the artificial liposomes formed by
surfactants from those prepared from natural phospholipids, the former are called
“vesicles”, while the name “liposomes” is reserved for the latter systems [14].
Fig. 2. Scheme of a lipid vesicle.
Liposomes formed from phospholipids can successfully mimic the dynamic,
fluid and semi-permeable natural bilayer[15]. Therefore, vesicles – in generalare widely used to study the properties of various type of membranes, cellular
processes (e.g. endo- and exocytosis, cell lysis, transport phenomena) or proteinmembrane lipid interactions [16,17], effect of biomolecules on phospholipid
bilayer [18-20] or the interaction of drugs with membrane components [21-23].
Although initially liposomes were used mainly to model the natural membranes,
with time their application has significantly broadened and now they are also
applied in medicine and pharmacy (drug delivery, preparation of less toxic drug
formulations [24,25]), in medical diagnostics, gene therapy, cosmetics, foodindustry, or in the environmental protection [26-28].
Although liposomes are easy to prepare and allow various spectroscopic
measurements, they suffer from several limitations. Firstly, the range over which
the lipid concentration can be varied without changing the surface curvature and
physical state is limited. It is not possible to regulate lipid lateral packing density
and lipid composition independently. Moreover, the physical state of
compositionally identical vesicles depends on the method of preparation. It is
also difficult to prepare a homogeneous (in size and layer number) vesicle
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51
suspension and to avoid a spontaneous fusion. Another severe disadvantage is a
small curvature radius that imposes strong constraints at the polar head level.
Monomolecular (Langmuir) films formed at the free surface of aqueous solutions
overcome all the above limitations as it has already been mentioned in the
Introduction. In addition, with the Langmuir technique contrary to liposomes, it
is possible to mimic similar conditions as in cellular membrane. It was found that
the pressure in biological membranes corresponds to the surface pressure of 3035 mN/m in the Langmuir experiment [29].
The use of monolayers as a membrane model system will be discussed
separately in the following paragraph. Before this, however, it is worthy
mentioning another membrane model, namely black lipids membranes (BLM),
so-called planar lipid bilayers (phospholipid molecules suspended over aperture
between two solutions phases; (Figure 3)), the formation of which were
originally reported at the same time as the lipid vesicles were discovered [30].
Fig. 3. Scheme of a black lipid membrane (BLM).
Although this kind of model membrane is certainly less popular as compared
to liposomes, due to its rather low stability and drastically limited number of
methods suitable for their analysis, it found application in studying the formation
of pores in phospholipid bilayer by selected biomolecules [31,32]. In order to
broaden the spectrum of experimental methods for BLM analysis, the
phospholipids bilayers have been deposited onto solid supports to form a group
of membrane models called surface-confined membrane systems [33], which
include the following: solid-supported lipid membranes, hybrid bilayers or
polymer-cushioned lipid bilayers (Figure 4) [33-35].
A phospholipid bilayer supported by solid substrates (solid-supported lipid
membranes) (Figure 4 A) can be obtained by spontaneous spreading of vesicles
onto solid surfaces or by transfer of the lipid monolayer formed at the air-water
interface to a solid support (Langmuir-Blodgett technique). The combination of
these two techniques is also frequently applied [30].
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The solid-supported lipid bilayers are more stable as compared to black lipids
membranes. The problem is the limited number of solid surfaces suitable for
supporting lipids and the existence of unfavourable interactions between
membrane components and solid surfaces. Similar disadvantages concern also
the hybrid bilayers, which are layers of phospholipids deposited on the top of
self-assembled (SAM) monolayers formed on metal surfaces. As regards SAM
monolayers, most frequently applied are thiols chemisorbed on metal surfaces
(like gold); other alternatives are SAM silanes chemisorbed on glass supports.
To avoid the influence from a supporting substrate and minimize the interactions
with the substrate, the polymer film (e.g. cellulose, chitosan, polyelectrolites)
can be introduced in-between [35]. However, these systems, named polymercushioned lipid bilayers, are known of defective structure and low stability.
Detailed description of the properties of the surface - confined membrane
systems is presented in an excellent review by E. Castellana and P. Cremer [30].
The foregoing model systems have been applied to studying the formation of
lipid rafts in membranes [36,37], charge transport properties of proteins [38], or
the influence of protein on lipid bilayers [39].
Fig. 4. The surface-confined membrane systems: A) solid-supported lipid membranes; B)
hybrid membranes; C) polymer-cushioned lipid bilayers
3. LANGMUIR MONOLAYERS AS MODEL OF MEMBRANES
The Langmuir monolayer technique is of special importance as regards
modelling of natural membranes. To prove, a bilayer structure of the cellular
membrane was just evidenced with the Langmuir method [4, 40].
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One – or multicomponent Langmuir monolayers formed at the air/water
interface by membrane lipids serve as a simple model for studying the properties
of individual membrane leaflets keeping their asymmetry and individuality
(Figure 5) [41].
Fig. 5. A Langmuir monolayer as a model of membrane leaflet.
By mixing the components in a certain proportion it is possible to study
various types of membranes. Additionally, by mixing lipids and film-forming
amphiphatic drugs or other molecules acting on membrane level in a Langmuir
monolayer, one may investigate the effects of these bioactive components on
membrane organization. Depending on the kind of a biomolecule, two different
methods can be applied.
For water soluble biomolecules the experiment is based on the compression
of a monolayer mimicking the natural membrane (composed of membrane
components, usually lipids, in a certain proportion) formed on the subphase
containing the dissolved biomolecule (see for example [42]. It is also frequent
that a solution containing the investigated biomolecule is injected into bulk
water, underneath the previously formed monolayer, compressed to a particular
surface pressure value. The dissolved biomolecule incorporate into the
monolayer (see for example [43]). The penetration of biomolecules into the
floating film causes the changes of the surface pressure values, which is
monitored and can be taken as a measure of interactions between the molecules.
When water-insoluble biomolecules are investigated, the approach is based
on forming mixed Langmuir monolayer by co-spreading of membrane
components and biomolecules onto water surface [44,45]. Changing the
proportion of monolayer components and analyzing the stability and miscibility
of the investigated mixed system with the simple functions or thermodynamic
parameters, the nature and strength of interaction between film molecules can be
estimated.
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K. Hąc-Wydro and P. Dynarowicz-Łątka
In general, the basis of the analysis of the interactions between monolayer
components is the surface pressure (π) – area (A) isotherms recorded upon film
compression. The analysis of the shape, course and position of the π/A curves
provides information on the monolayer state, area per film component or phase
transitions. The isotherms are also a starting point for calculation of the
compression modulus, area per molecule and excess area, excess thermodynamic
functions of mixing (free energy of mixing, total free energy of mixing, excess
entropy and enthalpy). Basing on the foregoing parameters it is possible to
conclude on the monolayer organisation, its state, phase separation, film
stability, and on the interactions between film components. Different approaches
used to characterize molecular interactions in monolayers are reviewed in Ref.
[46], while the paper by Gong et al. [47] can serve as a representative paper,
providing very useful experimental examples of the analysis of intermolecular
interactions.
Although the Langmuir monolayer technique allows mimicking the
membrane leaflets only independently, there is a strong correlation between
monolayers and bilayers prepared from cellular membrane components. It was
found [48] that the lipid monolayers and bilayers reveal similar properties
(pressure, area per lipid molecule, phase transition, elastic compressibility) at
surface pressures of 30–35 mN/m. Therefore, the results of Langmuir monolayer
experiments can be successfully linked to a bilayer system and provide essential
information not only on the behaviour of individual membrane components and
membrane properties, but also allow explaining the influence of biomolecules
(e.g. drugs, hormones) on model membranes by verifying the affinity of these
compounds to the respective membrane components and calculating their
interactions. Some examples of the application of the Langmuir technique to
modelling of natural membranes are presented below.
4. THE STUDY OF THE DRUGS MODE OF ACTION
A good example of amphiphatic drugs, extensively investigated with the
Langmuir monolayers technique are antifungal polyene antibiotics, represented
by amphotericin B (AmB). The mechanism of AmB activity has not been clearly
elucidated yet, however, the most widely accepted view holds that this polyene
antibiotic acts at the membrane level, forming membrane channels (pores) by
interacting with fungi membrane sterol (ergosterol), [49], which provokes the
lysis and finally death of fungi cells. Although AmB was found to be toxic also
to host cells, is still in clinical use since there are no alternative drugs of such a
broad spectrum of antifungal activity. Therefore, a lot of effort was put to
decrease the toxicity of polyenes. Over the years a number of AmB’s derivatives
have been synthesized [50-54] which were proved to be of decreased toxicity,
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together with AmB’s liposomal formulations. However, the following problems
concerning AmB remained unsolved: 1) its exact mechanism of action, 2) the
reason of its toxicity, 3) the mechanism of decreased toxicity found for AmB’ s
liposomal formulations and some of AmB derivatives. The Langmuir monolayer
technique helped in understanding of all the above questions. Namely, studies of
the Langmuir monolayers of AmB mixed with fungi sterol (ergosterol) and
mammalian sterol (cholesterol) proved that AmB interactions with both sterols
are of nearly similar order [55]. The observed low selectivity of AmB toward
both sterols explains AmB toxicity also to host cells, containing cholesterol.
Studies of the mixed systems of phospholipids and both sterols proved stronger
interactions of DPPC-cholesterol vs DPPC-ergosterol [43]. This implies that in
the presence of AmB, the antibiotic molecules can bound easier to ergosterol
than to cholesterol, which explains slightly stronger affinity of AmB to
ergosterol as compared to cholesterol, and in consequence, its increased toxicity
towards fungi cells (containing ergosterol) in comparison to mammalian cells
(containing cholesterol).
To explain the mechanism of lower toxicity of liposomal formulation of AmB
and reduced toxicity of some of AmB derivatives, the study of the interactions
between series of polyenes and phospholipids [55-63] were found to be of much
help. It came out that the antibiotic/phospholipid interactions affect the activity
and toxicity of the investigated drugs. Basing on Langmuir monolayers
experiments, the role of phospholipids in polyenes activity on both fungi and
human membranes was explained [55,59-63] and the mechanism of reduced
toxicity of polyenes liposomal formulation was suggested [57].
Similar experiments as performed for antifungal drugs are being carried out
for many other physiological compounds of amphiphatic structure, possessing
anti-inflammatory, analgesic or anticancer effect [42,64,65]. As far as antitumor
drugs are concerned, recently the scientists focused their attention on the group
of alkyl-lysophospholipids (ALP) represented by miltefosine (hexadecylphosphocholine), edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-,phosphocholine) as well as by perifosine (octadecylpipiridine) and ilmofosine (1-hexadecylthio-2-methoxymethyl-rac-glycero-3-phosphocholine) [66]. These compounds induce cell apoptosis, however, they differ from other chemotherapeutics
because they do not affect DNA, but target a cellular membrane [67]. Although
the mechanism of action of alkylphospholipids has not been elucidated so far, a
number of hypotheses concerning activity of these compounds (e.g. the
inhibition of phosphatidylcholines and sphingomyelin synthesis [68],
accumulation in plasma membrane [69], inhibition of cellular enzymes [70] or
incorporation into lipid rafts of tumor cells [68]) prove that they act on
membrane level [67]. The cellular membrane plays a fundamental role in ALPs’
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K. Hąc-Wydro and P. Dynarowicz-Łątka
mode of action due to the fact that these compounds exhibit a phospholipids-like
structure and can build-in natural membrane.
Current research concentrates on clarification of a significance of respective
membrane components in the mechanism of action of these drugs. Recently,
series of experiments have been done for monolayers containing miltefosine or
edelfosine mixed with major membrane lipids: cholesterol, phosphocholines and
phosphatidylethanolamines [71-76]. The obtained results show that membrane
phospholipids (DPPC, OPPE) at physiological conditions (pH = 6) interact
weakly with both miltefosine and edelfosine [73,74] which implies that they are
of low importance as regards their mechanism of action. On the other hand,
ALPs interact strongly with membrane sterol (cholesterol) [71,72,75] and form
surface complexes [71,75] These results allowed understanding in vitro
experiments on cell cultures, which showed that the presence of cholesterol in
excess lowers the uptake of ALPs.
5. THE INFLUENCE OF BIOMOLECULES ON MEMBRANES
Studies on the mechanism of action of drugs and their interactions with
membrane components are not the only examples of biomedical application of
the Langmuir monolayer technique. Apart from drugs, there is a large group of
membrane active compounds, the effect of which on the membrane can be
verified with the Langmuir films method.
Carotenoids, comprising nearly 600 fat-soluble pigments, are examples of
intensively studied biomolecules. Unfortunately carotenoids can be synthesized
only by plants and microorganism and therefore the presence of these
compounds in human organism is dependent on the diet. Within this group, the
investigations are focused mainly on β-carotene, lycopene, luteine and
zeaxanthin. Carotenoids possess antioxidant properties, are precursors of vitamin
A and its derivatives and have beneficial influence on human organism. They
prevent coronary vascular diseases, cancers, positively affect the immune system
and prevent eye diseases. The classification of carotenoids and their influence on
human organism were described in review article by Krinsky and Johnson [77].
Carotenoids play also an important role on biomembranes and this aspect was
discussed by Gruszecki and Strzałka in their review article [78]. In membranes,
carotenoids ensure protection against oxidation of unsaturated chains of
membrane lipids and in this way prevent cell damage. However, the
incorporation of carotenoids, depending on the structure of the molecule, may
change membrane properties e.g. permeability, fluidity or molecular packing.
The Langmuir monolayer experiments from carotenoids involved mainly studies
on the interactions between these compounds and membrane phosholipids
[79,80]. These investigations provided both the characteristics of the properties
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of carotenoids monolayers and thermodynamic description of the interactions
between carotenoids and membrane lipids, analysed in relation to the structure of
the investigated carotenoids. Basing on these results, the localization and
orientation of the respective carotenoids in membrane were discussed and
differences in physiological activity of these compounds were explained [80].
Similar experiments were performed for another well known antioxidant, namely
vitamin E (tocopherol) [81,82].
Both carotenoids and vitamin E are plant-derived compounds favourably
influencing the human body. Another group of compounds derived from plant
and possessing positive effect on human health are unsaturated fatty acids. These
compounds generally prevent heart diseases and possess anticancer and
antimicrobial properties. Polyunsaturated fatty acids: linoleic and α-linolenic
(omega-6 and omega-3 group, respectively) are known as the “essential” fatty
acids because they cannot be synthesized by human body and are derived only
from the diet. The fatty acids are also necessary to synthesis of the lipids forming
cellular membranes. With the Langmuir monolayer technique the interactions
between cholesterol and various saturated and unsaturated fatty acids were
studied in the context of anticholesterolemic properties of these compounds [83].
In addition, the influence of fatty acids on model cholesterol/phospholipids
membranes was investigated [84]. It is known that fatty acids are building blocks
of phospholipids molecules, however, are also present in membranes in nonesterified form (“free” fatty acids). The experiments performed in ternary
mixtures allow explaining the reasons of such a low proportion of non-esterified
fatty acids in membranes.
The capability of many biomolecules to form monomolecular layers at the
air/water interface opens the way to study their behaviour on the membrane
level. As indicated in this article, the Langmuir monolayer technique is a potent
method for mimicking of cellular membranes.
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